This invention relates to medicament respiratory delivery devices including pulmonary, intranasal and buccal respiratory delivery devices having more efficient delivery of a medicament to the respiratory system of a patient.
Inhalers and atomizers are now commonly used primarily to deliver various liquid medicaments via the patient""s or user""s nose or mouth. As used herein, xe2x80x9cmedicamentxe2x80x9d includes any powder or liquid medicament, drug or vaccine or combinations thereof which may be administered from an respiratory delivery device through the user""s nose or mouth, sometimes referred to herein as a medicament respiratory delivery device. More recently, the prior art has proposed unit dose disposable powder medicament delivery devices, such as disclosed in U.S. Pat. No. 5,215,221, wherein a predetermined quantity or unit dose of a powder medicament is sealed in a reservoir formed between opposed thermoplastic sheets and expressed or delivered by application of manual force to a thermoformed blister which, upon activation, breaks a burstable seal between the sheets at the entrance to the reservoir and fluidizes the powder medicament in the reservoir through a delivery tube. The sealed delivery tube is cut prior to use.
There are several considerations affecting the design and efficacy of medicament respiratory delivery devices. First, it is important to ensure that a predetermined quantity or dose of medicament is consistently delivered to the user with each application. Second, because respiratory therapy often requires numerous applications, the cost of providing the dosage should also be considered. Thus, it is desirable that the medicament respiratory delivery device consistently express substantially all of the medicament to the user and that the delivery device is not susceptible to user error in operation. Third, it is important that the medicament be properly disbursed or entrained in the conveying fluid. Further considerations include the operating complexity, cost of the device, portability and size of the delivery device. It would also be desirable in certain applications to provide a reusable delivery device with a disposable standard medicament cartridge containing a unit dose of medicament which can be easily handled and replaced in the delivery device by the user without error. In other applications, a disposable delivery device is desirable.
The embodiments of the medicament respiratory delivery devices and medicament cartridge of this invention provide a reproduceable, high level of clearance of medicament or emitted dose from the cartridge upon manual actuation of the device with modest gas pressure as well as improved efficiency in the delivery of that medicament.
The cartridge for a medicament respiratory delivery device of this invention includes a body having opposed ends, a passage through the body and through the opposed ends, a medicament stored in the passage and burstable or pierceable membranes covering and sealing the passage at the opposed ends of the body. In the preferred embodiments, the opposed ends of the cartridge body surrounding the passage are convex and the burstable membranes are stretched taut over the convex opposed ends and bonded thereto, sealing the passage. In one disclosed embodiment, the opposed ends of the body are frustoconical surrounding the passage and the membranes comprise a thin polyolefin film heat-sealed or fused to the opposed frustoconical ends of the body. The term polyolefin is understood to mean a polymer containing olefin units such as, for example, ethylene, propylene or 1-butene units or any other alpha-olefin. Polyolefin as used herein includes polyethylene, polypropylene, ethylene- .alpha. olefin copolymer, wherein the alpha olefin having from 3 to 20, preferably 4 to 8 carbon atoms, polyolefin copolymers made by polymerizing olefins in the presence of a metallocene catalyst, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, and ethylene-methyl acrylate copolymer. In particular, it is desirable to use polyethylene, such as low-density, linear-low-density, very-low-density, medium-density, or high-density polyethylene, or polypropylene, such as a polypropylene homopolymer, ethylene-propylene copolymer, or ethylene-propylene block copolymer.
In one preferred embodiment, the polymeric films which form the burstable membranes are preferentially oriented polyolefin films, preferably uniaxially oriented polyethylene films, angularly related, wherein the films oriented on the opposed ends of the cartridge are most preferably oriented at approximately right angles. It has been found by the applicant that burstable membranes formed of preferentially or uniaxially oriented polyolefin film, most preferably polyethylene film, wherein the films are oriented at approximately right angles, results in improved delivery of the medicament from the body passage or reservoir to the respiratory system of the user and results in a consistently greater emitted dose. Polyolefin films can be oriented by drawing in one or both mutually perpendicular directions in the plane of the film to impart strength thereto using methods known in the art. Oriented polyolefin films include machine direction and transverse direction orientation. Oriented polyolefin films include uniaxially or biaxially oriented films, with uniaxially films being preferred having a draw ratio of at least 1.2. Uniaxially-oriented films have properties to their advantage for use as the burstable membrane, including relatively high stiffness, as indicated by the tensile modulus in a particular direction, usually the machine direction, compared to the transverse direction. Properties of the oriented polyolefin film can be dependent to a certain degree on the particular process conditions under which the polyolefin film was manufactured. For example, a stiffer film with lower transverse burst pressure properties would result from an orientation process incorporating a larger machine direction orientation draw ratio. Thus, oriented polyolefins films can be tailored to provide an appropriate burst pressure property within a preferred film thickness range. Based upon computer modeling, consistently greater dosing is believed to result from turbulence or xe2x80x9cturningxe2x80x9d of the delivery fluid through the passage containing the medicament. Prototype testing indicates that the burstable membranes at the opposite ends of the cartridge in the delivery devices of this invention rupture nearly simultaneously using only a modest pressure. Where the membranes are preferentially or uniaxially oriented and perpendicular, the membranes each rupture in a slit near the center along the axis of the oriented films at approximately right angles to one another. This requires the fluid, such as a gas, to turn as the fluid is rapidly transmitted through the passage, entraining the medicament and expressing the entrained medicament through the slit formed in the second membrane. It has been found by the applicant that generally perpendicular orientation of the preferentially or uniaxially oriented films oriented at right angles resulted in an emitted dose of about 97%.
In another preferred embodiment, the burstable membranes are formed of a cast polyolefin copolymer of polyethylene and polyethylene methylacrylate copolymer film having a thickness of about 0.5 mil, wherein the films are stretched taut over the passage and heat sealed or fused to the opposed ends of the cartridge. Where the burstable membranes are formed of preferentially or uniaxially oriented polyethylene film, the film preferably has a thickness of about 1 mil. However, it is believed that the burstable membranes may also be formed of other polymers including, for example, polypropylene, acetate, polycarbonate, etc., wherein the film is preferably scored or embossed to reduce the required gas rupture pressure, thus having a rupture pressure of between 1.2 and 10 atmospheres, more preferably less than 5 atmospheres and most preferably between 1.5 and 4 atmospheres. Medicament cartridges employing such low burst pressure films allow for use of simple, manually actuated, pressurization mechanisms as described below. In one preferred embodiment of the cartridge for a medicament delivery device of this invention, the medicament passage or reservoir is generally cylindrical and the cartridge body is also generally cylindrical. An annular groove may be provided at the mid-portion of the body for ease of handling.
The methods of making a cartridge for a medicament respiratory delivery device of this invention includes forming a cartridge having first and second ends and a passage through the first and second ends of the cartridge; forming a thin polymeric film over the passage through the first end of the cartridge, sealing the passage through the first end; inserting a medicament into the passage through the second end of the cartridge; and applying a thin burstable polyolefin sheet over the second end of the cartridge having a burst pressure of less than 10 atmospheres, preferably less than 5 atmospheres, sealing the passage through the second end. In one preferred method of this invention, the method includes forming the cartridge from a polymer similar to the thin burstable polymeric sheet and bonding the polymeric sheet over the second end of the cartridge by heat bonding or fusing. Thus, a preferred method of forming the cartridge of this invention includes forming the cartridge from a polyolefin, preferably a polyethylene, and heat bonding a thin burstable polyolefin sheet to the second end of the cartridge by first stretching the film taut over the second end of the cartridge and then applying a heated die to the thin polyolefin film.
Based upon computer modeling, the highest medicament delivery rate is achieved using only one burstable polymeric membrane at the exit of the delivery device. This can be accomplished by removing the film sealing the first end of the cartridge prior to use, such as by piercing the membrane as disclosed in a copending application by the Applicant filed concurrently herewith. Where the cartridge includes burstable polymeric films over both ends of the cartridge, the most preferred embodiment of the method of this invention includes stretching taut polyolefin films over both ends of the cartridge prior to bonding the films to the opposed ends. In the most preferred embodiments, the cartridge is formed of a polymeric material having convex, preferably frustoconical, surfaces surrounding the passage and the film is stretched taut over the passage prior to bonding, thereby eliminating bowing or wrinkling of the film during heat sealing which may adversely affect the burst reproducibility, particularly where the fluid pressure is relatively low.
The embodiments of the medicament respiratory delivery device of this invention includes a housing having a chamber therein, an inlet port communicating with the chamber and an outlet port communicating with the chamber, preferably coaxially aligned with the inlet port. A cartridge is located within the housing chamber having opposed ends, a passage extending through the cartridge through the opposed ends, preferably generally coaxially aligned with the inlet and outlet ports of the housing, a medicament in the cartridge passage and burstable polymeric membranes covering the passage at the opposed ends of the cartridge. In one preferred embodiment of the medicament respiratory delivery device of this invention, the housing is formed of two releasably interconnected parts providing access to the chamber and replacement of the disposable cartridge. The gas inlet port includes an inlet tube communicating with the chamber for receipt of a collapsable fluid delivery device, such as a syringe barrel or compressible bulb. In one embodiment, the inlet tube includes a Luer connector adapted to receive a syringe barrel for supplying fluid or gas through the inlet tube to the cartridge.
In another preferred embodiment, the medicament respiratory delivery device is formed by thermoforming opposed polymeric sheets forming a chamber which encapsulates the medicament cartridge, inlet and outlet ports communicating with the chamber and a collapsible bulb at the inlet port which may comprise an integral thermoformed blister. In this embodiment, the body of the medicament cartridge preferably includes at least one and preferably two opposed integral flanges or wings, which are thermoformed between the sheets, assuring sealing of the chamber containing the cartridge. As described above, the burstable membrane at the outlet end of the cartridge preferably comprises a preferentially oriented polyolefin film, most preferably preferentially oriented polyethylene films at each end of the cartridge, wherein the films are oriented at approximately right angles, but may also comprise cast or embossed polyolefin films or other polymers.
The preferred embodiments of the medicament delivery device of this invention are particularly, but not exclusively, adapted for respiratory delivery including pulmonary, intranasal or buccal medicament delivery of a powder medicament, wherein the patient""s inspiratory flowrate is not the driving force or pressure behind the aerosilization of the powder medicament. The powder is dispersed by fluid pressure that ruptures the membranes on the opposed ends of the cartridge, creating a substantially instantaneous fluid stream through the cartridge, entraining the powder particles into the fluid, which disperses the medicament to the respiratory system of the patient. This reduces the necessity for coordination of the patient""s actuation of the device with the inspiratory flowrate and allows for less dependence of quantity of medicament delivered on patent""s inspiration rate. As will be understood, however, the medicament respiratory delivery device of this invention, particularly including the cartridge, can also be utilized for liquid medicament delivery.
In preferred embodiments of the medicament respiratory delivery device and cartridge it has now been found that the efficiency of delivery of medicament is improved allowing for the use of reduced dosages of medicament while still achieving the same results as a higher dosage.
The method of delivering a medicament to the respiratory system of this invention includes providing a medicament respiratory delivery device including a cartridge having opposed inlet and outlet ends, a passage containing a medicament extending through the cartridge through the inlet and outlet ends, a thin burstable membrane, preferably a polyolefin membrane having a thickness of between 0.3 and 1.5 mils and having a burst pressure of between 1.2 and 10 atmospheres, preferably less than 5 atmospheres, sealing the passage at the outlet end of the cartridge and a manually compressible fluid delivery device communicating with the inlet end of the cartridge, such as a collapsible bulb or syringe as described above. The method then includes compressing the manually compressible fluid delivery device to deliver fluid to the inlet of the capsule, rupturing the burstable membrane, entraining the medicament in the fluid in an improved manner, dislodging fine particles of the active agent from carrier particled in the medicament and delivering increased amount of fine particles of the medicament to the respiratory system of the user.
In the preferred embodiments, the cartridge of the medicament respiratory delivery device includes a thin polyolefin burstable membrane having a burst pressure of less than 5 atmospheres sealing the passage at the inlet and outlet ends of the cartridge and the method then includes compressing the manually compressible fluid delivery device to deliver fluid to the burstable membrane at the inlet end of the cartridge, substantially simultaneously rupturing both burstable membranes, entraining the medicament in the fluid and delivering the medicament to the respiratory system of the user. In the most preferred embodiment, the passage at the inlet and outlet ends of the cartridge are sealed with preferentially oriented polyolefin films, wherein the orientation of the films are angularly related to each other and the method then includes delivering fluid to the inlet end of the cartridge, rupturing the film at the inlet end of the cartridge in a first slit, substantially simultaneously rupturing the burstable membrane at the outlet end in a second slit angularly related to the first slit, creating turbulence in the passage, entraining the medicament and expressing the medicament through the outlet end to the respiratory system of the user.
Other advantages and meritorious features of the medicament respiratory delivery device, medicament cartridge and method of making a cartridge for a medicament delivery device of this invention will be more filly understood from the following description of the preferred embodiments, the claims and the appended drawings, a brief description of which follows.